Study: H5N1 potential for mutation raises human risk

DAILY Bite

• A single mutation (Gln226Leu) in H5N1 could enable human-to-human transmission by binding to upper respiratory tract receptors.

• H5N1, detected in North America in 2021, has spread to 282 U.S. dairy herds and caused human infections without documented human-to-human transmission.

• While the CDC assures that the current risk is low, the virus’ potential for mutations that favor upper respiratory tract transmission makes monitoring necessary. 

DAILY Discussion

A recent study suggests that a single mutation in the H5N1 strain of highly pathogenic avian influenza could enable the virus to attach more effectively to human cell receptors, significantly increasing the risk of human-to-human transmission.

The H5N1 strain responsible for the current outbreak in the United States, was first detected in North America in 2021. This group of organisms has demonstrated a remarkable ability to infect a broad range of species, including wild birds, marine mammals, and humans.

By 2024, it had spread to at least 282 dairy herds across 14 U.S. states, with several confirmed human infections. Although no cases of human-to-human transmission have been documented, the virus’s high mortality rates in poultry and adaptability have raised serious concerns among scientists.

Recent reports of a domestic pig case and human cases, including a teenager in Canada hospitalized in critical condition with a strain of H5N1 carrying mutations at key positions, have come at a similar time to this study’s release. 

“For a new pandemic H5N1 virus, we know that it has to switch receptor specificity from avian-type to human-type. So what will it take?” asked James Paulson, a study co-author and biochemist at Scripps Research. The study published today in Science found that a single mutation — a substitution at the 226th amino acid in the hemagglutinin (HA) protein — could enable H5N1 to bind to human-type receptors located in the upper respiratory tract. This discovery marks a potential one-step path for the virus to become more transmissible among humans.

The research team, led by Ting-Hui Lin, engineered targeted mutations in the receptor-binding site of the HA protein from a Texas-origin H5N1 strain linked to human infection. Their work revealed that the Gln226Leu mutation alone was sufficient to switch the virus’s binding preference from avian to human receptors. Furthermore, the addition of a second mutation, Asn224Lys, enhanced the virus’s binding to human receptors to levels comparable to those seen in the 2009 H1N1 “swine flu” pandemic strain.

“This was surprising. It was just this single mutation [that] was sufficient to switch the receptor specificity,” said Ian Wilson, a co-author and structural biologist at Scripps Research. Past studies have shown that multiple mutations are typically required for such a shift, making this finding particularly concerning.

H5N1’s current preference for receptors in the lower respiratory tract has limited its ability to spread efficiently among humans, as infections primarily cause severe respiratory disease, such as viral pneumonia. However, if the virus acquires mutations that favor upper respiratory tract receptors, it could lead to common cold-like symptoms and increased transmissibility via coughing and sneezing.

The Centers for Disease Control is overseeing the situation and working to monitor states and people with animal exposure. It says that the current health risk is low.

“The magic that we hope doesn’t happen is that all of those things come together so that we have that first [human-to-human] transmission and that becomes a pandemic virus,” Paulson said. The findings emphasize the urgent need for heightened surveillance of H5N1 mutations and proactive measures to mitigate the risks of a future influenza pandemic.